The discovery of the sweetness of the dipeptide .alpha.-L-aspartyl-L-phenylalanine methylester was reported in 1969 by R. H. Mazur et al (Jour. Amer. Chem. Soc., 91, 2684, 1969). Since then, several methods have been developed for preparing the compound (see, for example, U.S. Pat. Nos. 3,475,403; 3,833,553; 3,798,206; 3,769,333; and 3,933,781).
In U.S. Pat. No. 3,475,403, Mazur et al react N-benzyloxycarbonyl-L-aspartic acid .alpha.-.rho.-nitrophenol and .beta.-benzylester and L-tyrosine methylester, to produce the .beta.-benzyl-N-benzyloxycarbonyl-L-aspartyl-L-tyrosine methylester. In U.S. Pat. No. 3,933,781, L-phenylalanine and N-formyl-L-aspartic anhydride are used to form N-formyl-.alpha.-L-aspartyl-L-phenylalanine which is deformylated and then esterified to obtain the methylester compound.
The prior-art methods typically require a number of process steps and the use of various expensive reagents, resulting in a high cost for the .alpha.-L-aspartyl-L-phenylalanine dipeptide ester.
U.S. patent application Ser. No. 150,881, filed May 27, 1980, discloses the preparation of .alpha.-L-aspartyl-L-phenylalanine alkyl esters, particularly the methylester sweetener compound, in high yields; for example, over 70%, and without substantial racemization and isomer formation of the nonsweetener isomeric compound. The process comprises: reacting the free alpha-carboxyl group of an L-aspartate compound in which the .beta.-carboxyl group and the amino group are blocked with the free amino group of an alkyl ester of L-phenylalanine, to provide an L-aspartyl-L-phenylalanine-coupled compound; and hydrogenating the coupled compound, to provide an .alpha.-L-aspartyl-L-phenylalanine alkyl ester.